16-50711288-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001370466.1(NOD2):c.1296C>T(p.Arg432=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 1,613,584 control chromosomes in the GnomAD database, including 49,664 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 3255 hom., cov: 33)

Exomes 𝑓: 0.24 ( 46409 hom. )

Consequence

NOD2
NM_001370466.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.0500

Variant links:

Genes affected

NOD2 (HGNC:5331): (nucleotide binding oligomerization domain containing 2) This gene is a member of the Nod1/Apaf-1 family and encodes a protein with two caspase recruitment (CARD) domains and six leucine-rich repeats (LRRs). The protein is primarily expressed in the peripheral blood leukocytes. It plays a role in the immune response to intracellular bacterial lipopolysaccharides (LPS) by recognizing the muramyl dipeptide (MDP) derived from them and activating the NFKB protein. Mutations in this gene have been associated with Crohn disease and Blau syndrome. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

NOD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 16-50711288-C-T is Benign according to our data. Variant chr16-50711288-C-T is described in ClinVar as [Benign]. Clinvar id is 319445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-50711288-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.05 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOD2	NM_001370466.1 linkuse as main transcript	c.1296C>T	p.Arg432=	synonymous_variant	4/12	ENST00000647318.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOD2	ENST00000647318.2 linkuse as main transcript	c.1296C>T	p.Arg432=	synonymous_variant	4/12		NM_001370466.1	P1	Q9HC29-2
NOD2	ENST00000300589.6 linkuse as main transcript	c.1377C>T	p.Arg459=	synonymous_variant	4/12	1			Q9HC29-1
NOD2	ENST00000641284.2 linkuse as main transcript	c.1296C>T	p.Arg432=	synonymous_variant, NMD_transcript_variant	4/6
NOD2	ENST00000646677.2 linkuse as main transcript	c.1296C>T	p.Arg432=	synonymous_variant, NMD_transcript_variant	4/13

Frequencies

GnomAD3 genomes

AF:

0.182

AC:

27624

AN:

152088

Hom.:

3253

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0624

Gnomad AMI

AF:

0.323

Gnomad AMR

AF:

0.181

Gnomad ASJ

AF:

0.234

Gnomad EAS

AF:

0.00868

Gnomad SAS

AF:

0.127

Gnomad FIN

AF:

0.159

Gnomad MID

AF:

0.282

Gnomad NFE

AF:

0.269

Gnomad OTH

AF:

0.220

GnomAD3 exomes

AF:

0.190

AC:

47482

AN:

250080

Hom.:

5769

AF XY:

0.197

AC XY:

26661

AN XY:

135424

show subpopulations

Gnomad AFR exome

AF:

0.0584

Gnomad AMR exome

AF:

0.124

Gnomad ASJ exome

AF:

0.245

Gnomad EAS exome

AF:

0.00561

Gnomad SAS exome

AF:

0.144

Gnomad FIN exome

AF:

0.161

Gnomad NFE exome

AF:

0.270

Gnomad OTH exome

AF:

0.230

GnomAD4 exome

AF:

0.240

AC:

351405

AN:

1461378

Hom.:

46409

Cov.:

AF XY:

0.239

AC XY:

174102

AN XY:

727016

show subpopulations

Gnomad4 AFR exome

AF:

0.0573

Gnomad4 AMR exome

AF:

0.130

Gnomad4 ASJ exome

AF:

0.240

Gnomad4 EAS exome

AF:

0.00338

Gnomad4 SAS exome

AF:

0.147

Gnomad4 FIN exome

AF:

0.162

Gnomad4 NFE exome

AF:

0.271

Gnomad4 OTH exome

AF:

0.218

GnomAD4 genome

AF:

0.182

AC:

27631

AN:

152206

Hom.:

3255

Cov.:

AF XY:

0.177

AC XY:

13150

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.0624

Gnomad4 AMR

AF:

0.180

Gnomad4 ASJ

AF:

0.234

Gnomad4 EAS

AF:

0.00870

Gnomad4 SAS

AF:

0.128

Gnomad4 FIN

AF:

0.159

Gnomad4 NFE

AF:

0.269

Gnomad4 OTH

AF:

0.220

Alfa

AF:

0.246

Hom.:

10603

Bravo

AF:

0.177

Asia WGS

AF:

0.0730

AC:

260

AN:

3478

EpiCase

AF:

0.280

EpiControl

AF:

0.273

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 32% of patients studied by a panel of primary immunodeficiencies. Number of patients: 31. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Regional enteritis;C5201146:Blau syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Inflammatory bowel disease 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Blau syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

Cadd

Benign

1.7

Dann

Benign

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over